Antibiotic resistance among bacterial pathogens is on the rise, and is becoming a global health crisis. One emerging mechanism of antibiotic resistance is conferred by the Cfr protein, which catalyzes the methylation of carbon 8 of adenosine 2503 in 23S bacterial rRNA. Worryingly, this simple modification renders bacteria resistant to a number of classes of antibiotics currently in use that target the ribosome, includin phenicols, lincosamides, oxazolidinones, pleuromutilins, streptogramin A, and the macrolides josamycin and spiramycin. Moreover, resistance is conferred to linezolid, a synthetic oxazolidinone that is indicated for infections caused by a number of Gram-positive bacteria, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant streptococci, as well as some Gram-negative bacteria. Cfr uses a unique, radical-dependent, mechanism to catalyze methylation of its target, using S-adenosylmethionine (SAM) both as the source of the appended methyl carbon and as a radical initiator in the reaction. Unlike all other SAM- dependent enzymes, Cfr and other members of the family of enzymes in which it resides, dubbed the radical SAM superfamily, use a unique iron ion of a [4Fe-4S] as a major binding determinant for SAM. The work described herein focuses on generating inhibitors of Cfr that are engineered to take advantage of this novel binding mode. Strategies include structure-based design that is informed by computational docking as well as high throughput methods. It is hoped that these initial efforts will form the basis of a more comprehensive undertaking once these strategies are validated for this class of enzymes. It is clear that immediate action is required to prevent further spread of a resistance mechanism that has the ability to cripple the world's arsenal of clinically relevant antibiotics.